Veterans develop chronic kidney disease (CKD) at a significantly higher rate than the general population. The metabolic derangements associated with CKD lead to dramatic bone loss and a significant increased risk of fracture. More devastating than simply having increased fractures is that the risk of mortality associated with skeletal fracture, this is significantly higher in patiets with CKD compared to other patients that fracture. Collectively, this means our veterans are at risk of dying because of the skeletal complications of CKD. Clinical data regarding the effectiveness of controlling bone disease in CKD patients are limited and a call has been made for more data regarding safety and efficacy of bone agents in the setting of CKD. Surprisingly, there is also a paucity of pre-clinical data concerning how clinically relevant drugs affect skeletl properties in CKD. The goal of this project is to understand how potential clinical therapies affec skeletal health in a pre- clinical model of CKD. To achieve this goal we will use a slowly progressive animal model of kidney disease, the Cy/+ rat. Our group has shown that this pre-clinical model parallels the human disease in its development of disturbed mineral homeostasis and bone fragility. This means the results from this work will have high translational capacity to the clinic. In Aim 1 we will determine how altered kidney function associated with CKD (both high and low turnover disease) changes the skeletal distribution of bisphosphonate. Bisphosphonates are the most commonly used drug for treatment of metabolic bone disease yet they have not been used in CKD due to concern over drug accumulation. In a series of experiments we will administer fluorescent bisphosphonate to normal animals and those with CKD to allow mapping of drug distribution both at a bulk level (concentrations among bones) and at a tissue level (depth of penetration from bone surfaces). These experiments will help us to understand how altered kidney function influences drug accumulation and determine how this differs among dosing regimens. This will provide key data regarding dosing regimens of bisphosphonates. In Aim 2 we will determine if more frequent, low dose bisphosphonate treatment is more effective than a single dose in suppressing remodeling and preserving bone mass/mechanics. These experiments are based on our preliminary data showing that a single bolus dose of bisphosphonate is ineffective in controlling CKD-induced bone disease. Animals with CKD will be treated with a single dose of bisphosphonate, a weekly dose of bisphosphonate (which over the 10 week period equals the single bolus dose), or saline. The primary outcomes will be determined by skeletal analyses (bone density, architecture/geometry, structural/material biomechanical properties, histomorphometry). Biochemical measurements and renal function will also be assessed to assure these dose regimens do not adversely affect kidney function. Finally, in Aim 3 we will determine if combination treatment with bisphosphonates and raloxifene is more effective in normalizing bone of CKD animals compared to either monotherapy. Although bisphosphonate treatment is the goal-standard for treating various skeletal diseases, and we hypothesize they can be effective in the setting of CKD, their use is not expected to completely normalize bone mechanical properties in CKD because we have shown CKD leads to an intrinsic deficit in bones' material properties. We have further shown that raloxifene, a FDA-approved agent for treating bone, specifically benefits material properties and that when combined with bisphosphonate can improve mechanical properties more than either monotherapy alone. This experiment will treat CKD rats with bisphosphonate, raloxifene, bisphosphonate + raloxifene, or saline. The primary outcomes will match those of Aim 2 with additional in-depth analyses of tissue material properties (collagen cross-links, morphology, mechanics; bone hydration, bone mineralization). These data will serve as a platform on which to build a clinical regimen for reducing the skeletal burden and improving the quality of life of veterans suffering from CKD.